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United States Patent |
6,204,230
|
Taylor
,   et al.
|
March 20, 2001
|
Antibacterial compositions containing a solvent, hydrotrope, and surfactant
Abstract
Antibacterial compositions having excellent antibacterial effectiveness are
disclosed. The antibacterial compositions contain a polyhydric solvent, a
hydrotrope, a surfactant, an optional antibacterial agent, and water.
Inventors:
|
Taylor; Timothy J. (Phoenix, AZ);
Seitz, Jr.; Earl P. (Scottsdale, AZ)
|
Assignee:
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The Dial Corporation (Scottsdale, AZ)
|
Appl. No.:
|
467716 |
Filed:
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December 21, 1999 |
Current U.S. Class: |
510/131; 510/130; 510/237; 510/382; 510/386; 510/387; 510/388; 510/426; 510/427; 510/432; 510/503 |
Intern'l Class: |
C11D 003/48; C11D 001/83; C11D 003/43 |
Field of Search: |
510/130,131,237,382,386,387,388,432,503,426,427
|
References Cited
U.S. Patent Documents
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|
4093745 | Jun., 1978 | Wood et al. | 424/358.
|
4111844 | Sep., 1978 | Polony et al. | 252/106.
|
4350605 | Sep., 1982 | Hughett | 252/305.
|
4518517 | May., 1985 | Eigen et al. | 252/107.
|
4666615 | May., 1987 | Disch et al. | 252/11.
|
4675178 | Jun., 1987 | Klein et al. | 424/65.
|
4702916 | Oct., 1987 | Geria | 424/400.
|
4822602 | Apr., 1989 | Sabatelli | 424/65.
|
4832861 | May., 1989 | Resch | 252/106.
|
4851214 | Jul., 1989 | Walters et al. | 424/65.
|
4954281 | Sep., 1990 | Resch | 252/107.
|
4975218 | Dec., 1990 | Rosser | 252/117.
|
5006529 | Apr., 1991 | Resch | 514/721.
|
5057311 | Oct., 1991 | Kamegai et al. | 424/70.
|
5147574 | Sep., 1992 | Mac Gilp et al. | 252/108.
|
5158699 | Oct., 1992 | MacGilp et al. | 252/132.
|
5234618 | Aug., 1993 | Kamegai et al. | 252/106.
|
5415810 | May., 1995 | Lee et al. | 252/545.
|
5417875 | May., 1995 | Nozaki | 252/106.
|
5441671 | Aug., 1995 | Cheney et al. | 252/549.
|
5462736 | Oct., 1995 | Rech et al. | 424/401.
|
5480586 | Jan., 1996 | Jakubicki et al. | 252/545.
|
5635462 | Jun., 1997 | Fendler et al. | 510/131.
|
5635468 | Jun., 1997 | Fowler et al. | 510/406.
|
5635469 | Jun., 1997 | Fowler et al. | 510/406.
|
5646100 | Jul., 1997 | Haugk et al. | 510/131.
|
5653970 | Aug., 1997 | Vermeer | 424/70.
|
5681802 | Oct., 1997 | MacGilp et al. | 252/132.
|
5716626 | Feb., 1998 | Sakurai et al. | 424/401.
|
5728756 | Mar., 1998 | Gaffar et al. | 524/139.
|
5730963 | Mar., 1998 | Hilliard, Jr. et al. | 424/65.
|
5824650 | Oct., 1998 | De Lacharriere et al. | 514/15.
|
5837272 | Nov., 1998 | Fierro, Jr. et al. | 424/401.
|
5851974 | Dec., 1998 | Sandhu | 510/235.
|
5863524 | Jan., 1999 | Mason et al. | 424/65.
|
5871718 | Feb., 1999 | Lucas et al. | 424/65.
|
5888524 | Mar., 1999 | Cole | 424/402.
|
5919438 | Jul., 1999 | Saint-Leger | 424/70.
|
5955408 | Sep., 1999 | Kaiser et al. | 510/131.
|
5985294 | Nov., 1999 | Peffly | 424/401.
|
Foreign Patent Documents |
195 30 833 A1 | Feb., 1996 | DE | .
|
0 505 935 | Sep., 1992 | EP | .
|
WO 95/09605 | Apr., 1995 | WO | .
|
WO 95/32705 | Dec., 1995 | WO | .
|
96/06152 | Feb., 1996 | WO.
| |
WO 96/06152 | Feb., 1996 | WO | .
|
97/46218 | Dec., 1997 | WO.
| |
WO 97/46218 | Dec., 1997 | WO | .
|
WO 98/0110 | Jan., 1998 | WO | .
|
WO 98/55097 | Dec., 1998 | WO | .
|
WO 98/55096 | Dec., 1998 | WO | .
|
Other References
PCT International Search Report PCT/US 00/15698 Jun. 07, 2000 ( The Dail
Corporation).
Allawala et al., Journal of the American Pharmaceutical Association, vol.
XLII, No. 5, pp. 267-275 (1953).
Mitchell, J. Pharm. Pharmacol, 16, pp. 533-537 (1964).
|
Primary Examiner: Gupta; Yogendra
Assistant Examiner: Boyer; Charles
Attorney, Agent or Firm: Marshall, O'Toole, Gerstein, Murray & Borun
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part of U.S. patent application Ser. No.
09/338,654, filed Jun. 23, 1999, now U.S. Pat. No. 6,107,261.
Claims
What is claimed is:
1. An antibacterial composition comprising:
(a) about 1% to about 50%, by weight, of a polyhydric solvent;
(b) about 1% to about 50%, by weight, of a hydrotrope;
(c) about 1% to about 25%, by weight, of a surfactant;
(d) 0% to about 5%, by weight, of a phenolic antimicrobial agent; and
(e) water,
wherein the weight ratio of hydrotrope-to-polyhydric solvent is about 1:1
to about 6:1, and
wherein the composition provides a log reduction against Gram positive
bacteria of at least 2 after 30 seconds of contact, as measured against S.
aureus, and a log reduction against Gram negative bacteria of at least 2.5
after 30 seconds of contact, as measured against E. coli.
2. The composition of claim 1 wherein the weight ratio of
hydrotrope-to-polyhydric solvent is about 1.5:1 to about 5:1.
3. The composition of claim 1 wherein the weight ratio of
hydrotrope-to-polyhydric solvent is about 2:1 to about 4:1.
4. The composition of claim 1 wherein the polyhydric solvent is present in
an amount of about 5% to about 25%, by weight.
5. The composition of claim 1 wherein the polyhydric solvent is present in
an amount of about 5% to about 15%, by weight.
6. The composition of claim 1 wherein the polyhydric solvent comprises a
diol, a triol, a polyol, or a mixture thereof.
7. The composition of claim 1 wherein the polyhydric solvent comprises
ethylene glycol, propylene glycol, glycerol, diethylene glycol,
di-propylene glycol, tripropylene glycol, nexylene glycol, 1,3-butylene
glycol, 1,4-butylene glycol, 1,2,6-hexanetriol, sorbitol, PEG-4, PEG-6, or
mixtures thereof.
8. The composition of claim 1 wherein the hydrotrope is present in an
amount of about 5% to about 30%, by weight.
9. The composition of claim 1 wherein the hydrotrope is present in an
amount of about 10% to about 30%, by weight.
10. The composition of claim 1 wherein the hydrotrope is selected from the
group consisting of sodium cumene sulfonate, ammonium cumene sulfonate,
ammonium xylene sulfonate, potassium toluene sulfonate, sodium toluene
sulfonate, sodium xylene sulfonate, toluene sulfonic acid, xylene sulfonic
acid, sodium polynaphthalene sulfonate, sodium polystyrene sulfonate,
sodium methyl naphthalene sulfonate, disodium succinate, and mixtures
thereof.
11. The composition of claim 1 wherein the surfactant is present in an
amount of about 2% to about 20%, by weight.
12. The composition of claim 1 wherein the surfactant is present in an
amount of about 2% to about 15%, by weight.
13. The composition of claim 1 wherein the surfactant is selected from the
group consisting of an anionic surfactant, a cationic surfactant, a
nonionic surfactant, an ampholytic surfactant, and mixtures thereof.
14. The composition of claim 1 wherein the surfactant comprising an anionic
surfactant.
15. The composition of claim 1 wherein the anionic surfactant is selected
from the group consisting of a C.sub.8 -C.sub.18 alkyl sulfate, a C.sub.8
-C.sub.18 fatty acid salt, a C.sub.8 -C.sub.18 alkyl ether sulfate having
one or two moles of ethoxylation, a C.sub.8 -C.sub.18 alkamine oxide, a
C.sub.8 -C.sub.18 sulfosuccinate, a C.sub.8 -C.sub.18 alkyl diphenyl oxide
disulfonate, a C.sub.8 -C.sub.18 alkyl carbonate, a C.sub.8 -C.sub.18
alphaolefin sulfonate, a methyl ester sulfonate, and mixtures thereof.
16. The composition of claim 1 wherein the phenolic antimicrobial agent is
present in an amount of about 0.01% to about 3%.
17. The composition of claim 1 wherein the phenolic antimicrobial agent is
present in an amount of about 0.01% to about 1%.
18. The composition of claim 16 wherein the phenolic antimicrobial agent is
present in an amount of at least 2% of saturation when measured at room
temperature.
19. The composition of claim 16 wherein the phenolic antimicrobial agent is
present in an amount of at least 25% of saturation when measured at room
temperature.
20. The composition of claim 16 wherein the phenolic antimicrobial agent is
present in an amount of at least 50% to 100% of saturation when measured
at room temperature.
21. The composition of claim 1 wherein the phenolic antibacterial agent is
selected from the group consisting of:
(a) a 2-hydroxydiphenyl compound having the structure
##STR8##
wherein Y is chlorine or bromine, Z is SO.sub.2 H, NO.sub.2, or C.sub.1
-C.sub.4 alkyl, r is 0 to 3, o is 0 to 3, p is 0 or 1, m is 0 or 1, and n
is 0 or 1;
(b) a phenol derivative having the structure
##STR9##
wherein R.sub.1 is hydro, hydroxy, C.sub.1 -C.sub.4 alkyl, chloro, nitro,
phenyl, or benzyl; R.sub.2 is hydro, hydroxy, C.sub.1 -C.sub.6 alkyl, or
halo; R.sub.3 is hydro, C.sub.1 -C.sub.6 alkyl, hydroxy, chloro, nitro, or
a sulfur in the form of an alkali metal salt or ammonium salt; R.sub.4 is
hydro or methyl, and R.sub.5 is hydro or nitro;
(c) a diphenyl compound having the structure
##STR10##
wherein X is sulfur or a methylene group, R.sub.1 and R'.sub.1 are hydroxy,
and R.sub.2, R'.sub.2, R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, and
R'.sub.5, independent of one another, are hydro or halo; and
(d) mixtures thereof.
22. The composition of claim 21 wherein the antibacterial agent comprises
triclosan, p-chloro-m-xylenol, or mixtures thereof.
23. The composition of claim 1 further comprising:
0% to about 20%, by weight, of an alcohol, and
0% to about 5%, by weight, of a gelling agent.
24. The composition of claim 23 wherein the alcohol is selected from the
group consisting of methanol, ethanol, isopropyl alcohol, n-butanol,
n-propyl alcohol, and mixtures thereof.
25. The composition of claim 23 wherein the gelling agent comprises a
natural polymer, a synthetic polymer, a derivative of a natural polymer,
and mixtures thereof.
26. The composition of claim 1 having a pH of about 5 to about 8.
27. The composition of claim 1 having a pH of about 6 to about 8.
28. The composition of claim 1 comprising:
(a) about 5% to about 15%, by weight, of the polyhydric solvent;
(b) about 2% to about 20%, by weight, of the hydrotrope; and
(c) about 5% to about 20%, by weight, of an anionic surfactant.
29. The composition of claim 28 further comprising about 0.05% to about 1%,
by weight, of a phenolic antibacterial agent.
30. The composition of claim 29 wherein the phenolic antibacterial agent is
present in an amount of at least 25% of saturation when measured at room
temperature.
31. The composition of claim 28 wherein the polyhydric solvent comprises
propylene glycol, dipropylene glycol, or a mixture thereof; the hydrotrope
comprises a xylene sulfonate; and the surfactant comprises a C.sub.8
-C.sub.18 alkyl sulfate.
32. A method of reducing a bacteria population on a surface comprising
contacting the surface with a composition of claim 1 for 30 seconds to
achieve a log reduction of at least 2 against S. aureus and a log
reduction of at least 2.5 against E. coli.
33. The method of claim 32 further comprising rinsing the composition from
the surface.
34. The method of claim 32 wherein the surface is a skin of a mammal.
35. The method of claim 32 wherein the surface is a hard, inanimate
surface.
36. The method of claim 32 wherein the composition contacts the surface for
60 seconds to achieve a jog reduction of at least 3 against S. aureus.
37. The method of claim 32 wherein the composition contacts the surface for
30 seconds to achieve a log reduction of at least 3.75 against E. coli.
Description
FIELD OF THE INVENTION
The present invention is directed to antibacterial compositions, like
personal care compositions, having improved antibacterial effectiveness.
More particularly, the present invention is directed to antibacterial
compositions comprising a polyhydric solvent, a hydrotrope, a surfactant,
and an optional antibacterial agent that provide a substantial reduction,
e.g., greater than 99%, in Gram positive and Gram negative bacterial
populations within one minute.
BACKGROUND OF THE INVENTION
Antibacterial personal care compositions are known in the art. Especially
useful are antibacterial cleansing compositions, which typically are used
to cleanse the skin and to destroy bacteria and other microorganisms
present on the skin, especially the hands, arms, and face of the user.
Another class of antibacterial personal care compositions is hand sanitizer
gels. This class of compositions is used primarily by medical personnel to
disinfect the hands and fingers. A hand sanitizer gel is applied to, and
rubbed into, the hands and fingers, and the composition is allowed to
evaporate from the skin.
Antibacterial compositions in general are used, for example, in the health
care industry, food service industry, meat processing industry, and in the
private sector by individual consumers. The widespread use of
antibacterial compositions indicates the importance consumers place on
controlling bacteria and other microorganism populations on skin. It is
important, however, that antibacterial compositions provide a substantial
and broad spectrum reduction in microorganism populations quickly and
without problems associated with toxicity and skin irritation.
In particular, antibacterial cleansing compositions typically contain an
active antibacterial agent, a surfactant, and various other ingredients,
for example, dyes, fragrances, pH adjusters, thickeners, skin
conditioners, and the like, in an aqueous carrier. Several different
classes of antibacterial agents have been used in antibacterial cleansing
compositions. Examples of traditional antibacterial agents include a
bisguanidine (e.g., chlorhexidine digluconate), diphenyl compounds, benzyl
alcohols, trihalocarbanilides, quaternary ammonium compounds, ethoxylated
phenols, and phenolic compounds, such as halo-substituted phenolic
compounds, like PCMX (i.e., p-chloro-m-xylenol) and triclosan (i.e.,
2,4,4'-trichloro-2'-hydroxydiphenylether). Present-day antimicrobial
compositions based on such antibacterial agents exhibit a wide range of
antibacterial activity, ranging from low to high, depending on the
microorganism to be controlled and the particular antibacterial
composition.
Most commercial antibacterial compositions, however, generally offer a low
to moderate antibacterial activity. Antibacterial activity is assessed
against a broad spectrum of microorganisms, including both Gram positive
and Gram negative microorganisms. The log reduction, or alternatively the
percent reduction, in bacterial populations provided by the antibacterial
composition correlates to antibacterial activity. A log reduction of 3-5
is most preferred, a 1-3 reduction is preferred, whereas a log reduction
of less than 1 is least preferred, for a particular contact time,
generally ranging from 15 seconds to 5 minutes. Thus, a highly preferred
antibacterial composition exhibits a 3-5 log reduction against a broad
spectrum of microorganisms in a short contact time.
It should be noted that high log reductions have been achieved at pH values
of 4 and 9, but such log reductions are attributed at least in part to
these relatively extreme pH values. Compositions having such pH values can
irritate the skin and other surfaces, and, therefore, typically are
avoided. It has been difficult to impossible to achieve a high log
reduction using an antibacterial composition having a neutral pH of about
5 to about 8, and especially about 6 to about 8.
For example, WO 98/01110 discloses compositions comprising triclosan,
surfactants, solvents, chelating agents, thickeners, buffering agents, and
water. WO 98/01110 is directed to reducing skin irritation by employing a
reduced amount of surfactant.
Fendler et al. U.S. Pat. No. 5,635,462 discloses compositions comprising
PCMX and selected surfactants. The compositions disclosed therein are
devoid of anionic surfactants and nonionic surfactants.
WO 97/46218 and WO 96/06152 disclose compositions based on triclosan,
organic acids or salts, hydrotropes, and hydric solvents.
EP 0 505 935 discloses compositions containing PCMX in combination with
nonionic and anionic surfactants, particularly nonionic block co-polymer
surfactants.
WO 95/32705 discloses a mild surfactant combination that can be combined
with antibacterial compounds, like triclosan.
WO 95/09605 discloses antibacterial compositions containing anionic
surfactants and alkylpolyglycoside surfactants.
WO 98/55096 discloses antimicrobial wipes having a porous sheet impregnated
with an antibacterial composition containing an active antimicrobial
agent, an anionic surfactant, an acid, and water, wherein the composition
has a pH of about 3.0 to about 6.0.
N. A. Allawala et al., J. Amer. Pharm. Assoc.--Sci. Ed., Vol. XLII, no. 5,
pp. 267-275, (1953) discusses the antibacterial activity of active
antibacterial agents in combination with surfactants.
A. G. Mitchell, J. Pharm. Pharmacol., Vol. 16, pp. 533-537, (1964)
discloses compositions containing PCMX and a nonionic surfactant that
exhibit antibacterial activity. The compositions disclosed in the Mitchell
publication exhibit antibacterial activity in at least 47 minutes contact
time, thus the compositions are not highly effective.
Prior disclosures rely upon the presence of a traditional active
antibacterial agent (e.g., a phenol compound) in the composition, but have
not addressed the issue of which composition ingredient in an
antibacterial composition actually provides bacterial control. Prior
compositions also have not provided an effective, fast, and broad spectrum
control of bacteria at a neutral pH of about 5 to about 8, particularly at
pH about 6 to about 8, and especially in the absence of an active
antibacterial agent.
An efficacious antibacterial composition has been difficult to achieve
because of the properties of the antibacterial agents and the effects of a
surfactant on an antibacterial agent. For example, several traditional
active antibacterial agents, like phenols, have an exceedingly low
solubility in water, e.g., triclosan solubility in water is about 5 to 10
ppm (parts per million). The solubility of the antibacterial agent is
increased by adding surfactants to the composition. However, an increase
in solubility of the antibacterial agent, and in turn, the amount of
antibacterial agent in the composition, does not necessarily lead to an
increased antibacterial efficacy.
Without being bound to any particular theory, it is theorized that the
addition of a surfactant increases antibacterial agent solubility, but
also typically reduces the availability of the antibacterial agent because
a surfactant in water forms micelles above the critical micelle
concentration of the surfactant. The critical micelle concentration varies
from surfactant to surfactant. The formation of micelles is important
because micelles have a lipophilic region that attracts and solubilizes
the antibacterial agent, which renders the antibacterial agent unavailable
to immediately contact bacteria, and thereby control bacteria in short
time period (i.e., one minute or less).
The antibacterial agent solubilized in the surfactant micelles will control
bacteria, but in relatively long time frames. The antibacterial agent, if
free in the aqueous solution and not tied up in the surfactant micelle
(i.e., is activated), is attracted to the lipophilic membrane of the
bacteria and performs its function quickly. If the antibacterial agent is
tied up in the surfactant micelle (i.e., is not activated), the
antibacterial agent is only slowly available and cannot perform its
function in a time frame that is practical for cleaning the skin.
In addition, antibacterial agent that is solubilized in the micelle is
readily washed from the skin during the rinsing process, and is not
available to deposit on the skin to provide a residual antibacterial
benefit. Rather, the antibacterial agent is washed away and wasted.
Accordingly, a need exists for an antibacterial composition that is highly
efficacious against a broad spectrum of Gram positive and Gram negative
bacteria in a short time period, and wherein the antibacterial activity is
attributed primarily, or solely, to the presence of composition
ingredients that are different from a traditional active antibacterial
agent. The present invention is directed to such antibacterial
compositions.
SUMMARY OF THE INVENTION
The present invention relates to antibacterial compositions that provide a
substantial reduction in Gram positive and Gram negative bacteria in less
than about one minute. More particularly, the present invention relates to
antimicrobial compositions containing a polyhydric solvent, a hydrotrope,
a surfactant, water, and an optional active antibacterial agent. In
preferred embodiments, the present invention relates to antimicrobial
compositions containing a polyhydric solvent, a hydrotrope, a surfactant,
water, and an active antibacterial agent, wherein the antibacterial agent
is present in an amount of at least 2% of saturation, when measured at
room temperature.
Accordingly, one aspect of the present invention is to provide an
antibacterial composition comprising:
(a) about 1% to about 50%, by weight, of a polyhydric solvent;
(b) about 1% to about 50%, by weight, of a hydrotrope;
(c) about 1% to about 25%, by weight, of a surfactant;
(d) 0% to about 5%, by weight, of an antimicrobial agent; and
(e) water.
Another aspect of the present invention is to provide an effective
antibacterial composition that is free of a traditional active
antibacterial agent, like a phenol, but includes a polyhydric solvent,
hydrotrope, and surfactant, as composition ingredients that effectively
and rapidly reduce bacterial populations.
Still another aspect of the present invention is to provide an efficacious
antibacterial composition containing a polyhydric alcohol, a hydrotrope,
and an anionic surfactant, and that is free of a traditional active
antibacterial agent.
Another aspect of the present invention is to provide an antibacterial
composition containing a polyhydric solvent, hydrotrope, and surfactant,
wherein the weight ratio of hydrotrope to polyhydric solvent is about 1:1
to about 6:1, and preferably about 2:1 to about 4:1, and the surfactant is
selected from the group consisting of an anionic surfactant, a cationic
surfactant, a nonionic surfactant, an ampholytic surfactant, and mixtures
thereof.
Another aspect of the present invention is to provide an antibacterial
composition containing a polyhydric solvent, a hydrotrope, a surfactant,
and an active antimicrobial agent, wherein active antibacterial agent is
present in an amount of at least 2%, and preferably at least 25%, of
saturation, when measured at room temperature.
Yet another aspect of the present invention is to provide an antibacterial
composition that exhibits a log reduction against Gram positive bacteria
(i.e., S. aureus) of at least 2 after 30 seconds of contact.
Still another aspect of the present invention is to provide an
antibacterial composition that exhibits a log reduction against Gram
negative bacteria (i.e., E. coli) of at least 2.5 after 30 seconds of
contact.
Another aspect of the present invention is to provide an antibacterial
composition that exhibits a substantial log reduction against Gram
positive and Gram negative bacteria, and has a pH of about 5 to about 8.
Another aspect of the present invention is to provide consumer products
based on an antibacterial composition of the present invention, for
example, a skin cleanser, a body splash, a surgical scrub, a wound care
agent, a hand sanitizer gel, a disinfectant, a mouth wash, a pet shampoo,
a hard surface sanitizer, and the like.
A further aspect of the present invention is to provide a method of
reducing the Gram positive and/or Gram negative bacteria populations on
animal tissue, including human tissue, by contacting the tissue, like the
dermis, with a composition of the present invention for a sufficient time,
such as about 15 seconds to 5 minutes, to reduce the bacteria level to a
desired level. The composition can be wiped or rinsed from the skin, or
can be allowed to remain on the skin to allow volatile components of the
composition to evaporate.
The above and other novel aspects and advantages of the present invention
are illustrated in the following, nonlimiting detailed description of the
preferred embodiments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Personal care products, which typically incorporate a traditional active
antibacterial agent, have been known for many years. Since the
introduction of antibacterial personal care products, many claims have
been made that such products provide antibacterial properties. However, to
be most effective, an antibacterial composition should provide a high log
reduction against a broad spectrum of organisms in as short a contact time
as possible.
As presently formulated, commercial liquid antibacterial soap compositions
provide a poor to marginal time kill efficacy, i.e., rate of killing
bacteria. Table 1 summarizes the kill efficacy of commercial products,
each of which contains about 0.2% to 0.3%, by weight, triclosan (i.e., a
traditional antibacterial agent).
TABLE 1
Time Kill Efficacy of Commercial Liquid Hand Soaps
Organism
(Log Reductions after
1 Minute Contact Time)
Gram Positive Gram negative Gram negative
Product S. aureus E. coli K. pneum.
Commercial 1.39 0.00 0.04
Product A
Commercial 2.20 0.00 0.01
Product B
Commercial 1.85 0.00 0.00
Product C
Present-day products especially lack efficacy against Gram negative
bacteria, such as E. coli, which are of particular concern to human
health. The present invention, therefore, is directed to antibacterial
compositions having an exceptionally high broad spectrum antibacterial
efficacy, as measured by a rapid kill of bacteria (i.e., time kill), which
is to be distinguished from persistent kill.
The present antibacterial compositions provide excellent time kill efficacy
compared to prior compositions. The efficacy of the present compositions
is surprising because, unlike prior compositions, the present compositions
are free of an active antibacterial agent or contain an active
antibacterial agent as an optional ingredient. The antibacterial efficacy
of a present invention is related to the presence of a polyhydric solvent,
a hydrotrope, and a surfactant. In preferred embodiments, the weight ratio
of hydrotrope to polyhydric solvent is about 1:1 to about 6:1. In
embodiments wherein an optional active antimicrobial agent is present, the
agent is present in an amount of at least 2%, and preferably at least 25%,
of saturation, when measured at room temperature.
With respect to "% saturation" of the optional active antimicrobial agent,
it has been discovered that the antimicrobial efficacy of an active agent
can be correlated to the rate at which the agent has access to an active
site on the microbe. The driving force that determines the rate of agent
transport to the site of action is the difference in chemical potential
between the site at which the agent acts and the external aqueous phase.
Alternatively stated, the microbicidal activity of an active agent is
proportional to its thermodynamic activity in the external phase.
Accordingly, thermodynamic activity, as well as concentration, are
important variables with respect to antimicrobial efficacy. As discussed
more fully hereafter, thermodynamic activity is conveniently correlated to
the percent saturation of the active antibacterial agent in the continuous
aqueous phase of the composition.
The % saturation of an active antibacterial agent in any composition,
including a surfactant-containing composition, ideally can be expressed
as:
% saturation=[C/C.sub.s ].times.100%
wherein C is the concentration of antibacterial agent in the composition
and C.sub.s is the saturation concentration of the antibacterial agent in
the composition at room temperature. The percent saturation, or
alternatively the relative thermodynamic activity or relative chemical
potential, of an antibacterial active agent dissolved in a
surfactant-containing composition is the same everywhere within the
composition. Thus, the terms percent saturation of the antibacterial agent
"in a composition," "in the aqueous continuous phase of a composition,"
and "in the micellar pseudophase of a composition" are interchangeable,
and are used as such throughout this disclosure.
Maximum antibacterial efficacy is achieved when the difference in
thermodynamic activities of the active antibacterial agent between the
composition and the target organism is maximized (i.e., when the
composition is more "saturated" with the active ingredient). A second
factor affecting antibacterial activity is the total amount of available
antibacterial agent present in the composition, which can be thought of as
the "critical dose." Thus, the two key factors affecting the antibacterial
efficacy of an active agent in a composition are: (1) its availability, as
dictated by its thermodynamic activity, i.e., percent saturation in the
continuous aqueous phase of a composition, and (2) the total amount of
available active agent in the solution.
An important ingredient in antibacterial cleansing compositions is a
surfactant, which acts as a solubilizer, cleanser, and foaming agent.
Surfactants affect the percent saturation of an antibacterial agent in
solution, or more importantly, affect the percent saturation of the active
agent in the continuous aqueous phase of the composition. This effect can
be explained in the case of a sparingly water-soluble antibacterial agent
in an aqueous surfactant solution, where the active agent is distributed
between the aqueous (i.e., continuous) phase and the micellar pseudophase.
For antibacterial agents of exceedingly low solubility in water, such as
triclosan, the distribution is shifted strongly toward the micelles (i.e.,
a vast majority of the triclosan molecules are present in surfactant
micelles, as opposed to the aqueous phase).
The ratio of surfactant to antibacterial agent directly determines the
amount of active agent present in the surfactant micelles, which in turn
affects the percent saturation of the active agent in the continuous
aqueous phase. It has been found that as the surfactant:active agent ratio
increases, the number of micelles relative to active molecules also
increases, with the micelles being proportionately less saturated with
active agent as the ratio increases. Since the active agent in the
continuous phase is in equilibrium with active agent in the micellar
pseudophase, as the saturation of antibacterial agent in the micellar
phase decreases, so does the saturation of the antibacterial agent in the
continuous phase. The converse is also true. Active agent solubilized in
the micellar pseudophase is not immediately available to contact the
microoganisms, and it is the percent saturation of active agent in the
continuous aqueous phase that determines the antibacterial activity of the
composition. The active agent present in the surfactant micelles, however,
can serve as a reservoir of active agent to replenish the continuous
aqueous phase as the active agent is depleted.
In contrast to prior antibacterial compositions that relied upon
traditional active antibacterial agents for efficacy, the present
compositions do not rely upon such active antibacterial agents, which are
present as optional ingredients. The present compositions rely upon a
combination of a polyhydric solvent, hydrotrope, and surfactant, and
preferably wherein the hydrotrope and polyhydric solvent are present in a
ratio of about 1:1 to about 6:1. If present, the optional antibacterial
agent is present in an amount of at least 2% of saturation, when measured
at room temperature.
The present compositions are antibacterial compositions having an improved
effectiveness against both Gram negative and Gram positive bacteria, and
that exhibit a rapid bacteria kill. As illustrated in the following
embodiments, an antibacterial composition of the present invention
comprises: (a) about 1% to about 50%, by weight, polyhydric solvent; (b)
about 1% to about 50%, by weight, of a hydrotrope; (c) about 0.1% to about
25%, by weight, of a surfactant; (d) 0% to about 5%, by weight, of an
antibacterial agent; and (e) water. The surfactant preferably is an
anionic surfactant. The identity of the surfactant, however, is not
limited, especially when the compositions have a weight ratio of
hydrotrope to polyhydric solvent of about 1:1 to about 6:1, and preferably
about 1.5:1 to about 5:1.
If an active antibacterial agent is present in the composition, the
composition has a percent saturation of antibacterial agent in the
continuous aqueous phase of at least about 2%, and preferably at least
about 25%, when measured at room temperature. The compositions exhibit a
log reduction against Gram positive bacteria of about 2 after 30 seconds
contact. The compositions exhibit a log reduction against Gram negative
bacteria of about 2.5 after 30 seconds contact.
Polyhydric Solvent
A polyhydric solvent is present in the antibacterial compositions in an
amount of about 1% to about 50%, and preferably about 5% to about 25%, by
weight of the composition. To achieve the full advantage of the present
invention, the polyhydric solvent is present in an amount of about 5% to
about 15% by weight of the composition.
As defined herein, the term "polyhydric solvent" is a water-soluble organic
compound containing two to six, and typically two or three, hydroxyl
groups. The term "water-soluble" means that the polyhydric solvent has a
water solubility of at least 0.1 g of polyhydric solvent per 100 g of
water at 25.degree. C. There is no upper limit to the water solubility of
the polyhydric solvent, e.g., the polyhydric solvent and water can be
soluble in all proportions.
The term "polyhydric solvent" therefore encompasses water-soluble diols,
triols, and polyols. Specific examples of polyhydric solvents include, but
are not limited to, ethylene glycol, propylene glycol, glycerol,
diethylene glycol, dipropylene glycol, tripropylene glycol, hexylene
glycol, 1,3-butylene glycol, 1,4-butylene glycol, 1,2,6-hexanetriol,
sorbitol, PEG-4, PEG-6, and similar polyhydroxy compounds.
Hydrotrope
In addition to the polyhydric solvent, an antibacterial composition of the
present invention contains a hydrotrope. The hydrotrope is present in an
amount up to the solubility of the hydrotrope in water at 25.degree. C.,
typically in an amount of about 1% to about 50%, and preferably about 5%
to about 30%, by weight of the composition. To achieve the full advantage
of the present invention, the hydrotrope is present in an amount of about
10% to about 30%, by weight of the composition.
A hydrotrope is a compound that has the ability to enhance the water
solubility of other compounds. A hydrotrope lacks surfactant properties,
and typically is a short-chain alkyl aryl sulfonate. Specific examples of
hydrotropes include, but are not limited to, sodium cumene sulfonate,
ammonium cumene sulfonate, ammonium xylene sulfonate, potassium toluene
sulfonate, sodium toluene sulfonate, sodium xylene sulfonate, toluene
sulfonic acid, and xylene sulfonic acid. Other useful hydrotropes include
sodium polynaphthalene sulfonate, sodium polystyrene sulfonate, sodium
methyl naphthalene sulfonate, and disodium succinate.
In preferred embodiments of the present invention, the weight ratio of
hydrotrope to polyhydric solvent is about 1:1 to about 6:1, and preferably
about 1.5:1 to about 5:1. To achieve the full advantage of the present
invention, the ratio of hydrotrope to polyhydric solvent is about 2:1 to
about 4:1. Within this weight ratio of hydrotrope to polyhydric solvent,
the identity of the surfactant is not limited. Outside of this weight
ratio of hydrotrope to polyhydric solvent, the preferred surfactant is an
anionic surfactant.
Surfactant
As stated above, in addition to the polyhydric solvent and hydrotrope, a
present antimicrobial composition also contains a surfactant. The
surfactant is present in an amount of about 1% to about 25%, and
preferably about 2% to about 20%, by weight, of the composition. To
achieve the full advantage of the present invention, the antibacterial
composition contains about 2% to about 15%, by weight, of the surfactant.
Ready-to-use compositions typically contain about 1% to about 10%,
preferably about 1.5% to about 5%, and most preferably, 1.5% to about 3%,
of a surfactant, by weight, of the composition. Concentrated compositions
suitable for dilution typically contain greater than about 5%, by weight,
of a surfactant.
In preferred embodiments, the amount of surfactant is determined such that,
if present, the percent saturation of the optional antibacterial agent in
the continuous aqueous phase of the composition is at least about 2%,
preferably at least about 25%, and most preferably at least about 50%.
The identity of the surfactant is not limited. In particular, when the
weight ratio of hydrotrope-to-polyhydric solvent is about 1:1 to about
6:1, the surfactant can be an anionic surfactant, a cationic surfactant, a
nonionic surfactant, or a compatible mixture of surfactants. Within this
weight ratio, the surfactant also can be an ampholytic or amphoteric
surfactant, which have anionic or cationic properties depending upon the
pH of the composition. Outside of this ratio, the preferred surfactant is
an anionic surfactant.
The antibacterial compositions, therefore, preferably contain an anionic
surfactant generally having a hydrophobic moiety, such as a carbon chain
including about 8 to about 30 carbon atoms, and particularly about 12 to
about 20 carbon atoms, and further has a hydrophilic moiety, such as
sulfate, sulfonate, carbonate, phosphate, or carboxylate. Often, the
hydrophobic carbon chain is etherified, such as with ethylene oxide or
propylene oxide, to impart a particular physical property, such as
increased water solubility or reduced surface tension to the anionic
surfactant.
Therefore, suitable anionic surfactants include, but are not limited to,
compounds in the classes known as alkyl sulfates, alkyl ether sulfates,
alkyl ether sulfonates, sulfate esters of an alkylphenoxy polyoxyethylene
ethanol, alpha-olefin sulfonates, beta-alkoxy alkane sulfonates, alkylaryl
sulfonates, alkyl monoglyceride sulfates, alkyl monoglyceride sulfonates,
alkyl carbonates, alkyl ether carboxylates, fatty acids, sulfosuccinates,
sarcosinates, octoxynol or nonoxynol phosphates, taurates, fatty taurides,
fatty acid amide polyoxyethylene sulfates, isethionates, or mixtures
thereof. Additional anionic surfactants are listed in McCutcheon's
Emulsifiers and Detergents, 1993 Annuals, (hereafter McCutcheon's),
McCutcheon Division, MC Publishing Co., Glen Rock, N.J., pp. 263-266,
incorporated herein by reference. Numerous other anionic surfactants, and
classes of anionic surfactants, are disclosed in Laughlin et al. U.S. Pat.
No. 3,929,678, incorporated herein by reference.
Especially preferred anionic surfactants contain no more than two moles of
ethoxylation and are selected from the following classes of surfactants: a
C.sub.8 -C.sub.18 alkyl sulfate, a C.sub.8 -C.sub.18 fatty acid salt, a
C.sub.8 -C.sub.18 alkyl ether sulfate having one or two moles of
ethoxylation, a C.sub.8 -C.sub.18 alkamine oxide, a C.sub.8 -C.sub.18
alkoyl sarcosinate, a C.sub.8 -C.sub.18 sulfoacetate, a C.sub.8 -C.sub.18
sulfosuccinate, a C.sub.8 -C.sub.18 alkyl diphenyl oxide disulfonate, a
C.sub.8 -C.sub.18 alkyl carbonate, a C.sub.8 -C.sub.18 alpha-olefin
sulfonate, a methyl ester sulfonate, and mixtures thereof. The C.sub.8
-C.sub.18 alkyl group contains eight to sixteen carbon atoms, and can be
straight chain (e.g., lauryl) or branched (e.g., 2-ethylhexyl). The cation
of the anionic surfactant can be an alkali metal (preferably sodium or
potassium), ammonium, C.sub.1 -C.sub.4 alkylammonium (mono-, di-, tri), or
C.sub.1 -C.sub.3 alkanolammonium (mono-, di-, tri). Lithium and alkaline
earth cations (e.g., magnesium) can be used, but antibacterial efficacy is
reduced.
Specific preferred anionic surfactants include, but are not limited to,
lauryl sulfates, octyl sulfates, 2-ethylhexyl sulfates, lauramine oxide,
decyl sulfates, tridecyl sulfates, cocoates, lauroyl sarcosinates, lauryl
sulfosuccinates, linear C.sub.10 diphenyl oxide disulfonates, lauryl
sulfosuccinates, lauryl ether sulfates (1 and 2 moles ethylene oxide),
myristyl sulfates, oleates, stearates, tallates, ricinoleates, cetyl
sulfates, and similar surfactants. Additional examples of surfactants can
be found in "CTFA Cosmetic Ingredient Handbook," J. M. Nikitakis, ed., The
Cosmetic, Toiletry and Fragrance Association, Inc., Washington, D.C.
(1988) (hereafter CTFA Handbook), pages 10-13, 42-46, and 87-94,
incorporated herein by reference.
The antibacterial compositions also can contain nonionic surfactants.
Typically, a nonionic surfactant has a hydrophobic base, such as a long
chain alkyl group or an alkylated aryl group, and a hydrophilic chain
comprising a sufficient number (i.e., 1 to about 30) of ethoxy and/or
propoxy moieties. Examples of classes of nonionic surfactants include
ethoxylated alkylphenols, ethoxylated and propoxylated fatty alcohols,
polyethylene glycol ethers of methyl glucose, polyethylene glycol ethers
of sorbitol, ethylene oxide-propylene oxide block copolymers, ethoxylated
esters of fatty (C.sub.8 -C.sub.18) acids, condensation products of
ethylene oxide with long chain amines or amides, and mixtures thereof.
Exemplary nonionic surfactants include, but are not limited to, methyl
gluceth-10, PEG-20 methyl glucose distearate, PEG-20 methyl glucose
sesquistearate, C.sub.11-15 pareth-20, ceteth-8, ceteth-12, dodoxynol-12,
laureth-15, PEG-20 castor oil, polysorbate 20, steareth-20,
polyoxyethylene-10 cetyl ether, polyoxyethylene-10 stearyl ether,
polyoxyethylene-20 cetyl ether, polyoxyethylene-10 oleyl ether,
polyoxyethylene-20 oleyl ether, an ethoxylated nonylphenol, ethoxylated
octylphenol, ethoxylated dodecylphenol, or ethoxylated fatty (C.sub.6
-C.sub.22) alcohol, including 3 to 20 ethylene oxide moieties,
polyoxyethylene-20 isohexadecyl ether, polyoxyethylene-23 glycerol
laurate, polyoxy-ethylene-20 glyceryl stearate, PPG-10 methyl glucose
ether, PPG-20 methyl glucose ether, polyoxyethylene-20 sorbitan
monoesters, polyoxyethylene-80 castor oil, polyoxyethylene-15 tridecyl
ether, polyoxy-ethylene-6 tridecyl ether, laureth-2, laureth-3, laureth-4,
PEG-3 castor oil, PEG 600 dioleate, PEG 400 dioleate, and mixtures
thereof.
Numerous other nonionic surfactants are disclosed in McCutcheon's
Detergents and Emulsifiers, 1993 Annuals, published by McCutcheon
Division, MC Publishing Co., Glen Rock, N.J., pp. 1-246 and 266-272; in
the CTFA International Cosmetic Ingredient Dictionary, Fourth Ed.,
Cosmetic, Toiletry and Fragrance Association, Washington, D.C. (1991)
(hereinafter the CTFA Dictionary) at pages 1-651; and in the CTFA
Handbook, at pages 86-94, each incorporated herein by reference.
In addition to anionic and nonionic surfactants, cationic, ampholytic, and
amphoteric surfactants can be used in the antimicrobial compositions.
Cationic surfactants include amine oxides and amidoamine oxides, like
cocamine oxide, decylamine oxide, and myristyl amine oxide, for example.
Ampholytic surfactants can be broadly described as derivatives of secondary
and tertiary amines having aliphatic radicals that are straight chain or
branched, and wherein one of the aliphatic substituents contains from
about 8 to 18 carbon atoms and at least one of the aliphatic substituents
contains an anionic water-solubilizing group, e.g., carboxy, sulfonate, or
sulfate. Examples of compounds falling within this description are sodium
3-(dodecylamino)propionate, sodium 3-(dodecylamino)-propane-1-sulfonate,
sodium 2-(dodecylamino)ethyl sulfate, sodium
2-(dimethylamino)octadecanoate, disodium
3-(N-carboxymethyl-dodecylamino)propane-1-sulfonate, disodium
octadecyliminodiacetate, sodium 1-carboxymethyl-2-undecylimidazole, and
sodium N,N-bis(2-hydroxyethyl)-2-sulfato-3-dodecoxypropylamine.
More particularly, one class of ampholytic surfactants include sarcosinates
and taurates having the general structural formula
##STR1##
wherein R.sup.1 is C.sub.11 through C.sub.21 alkyl, R.sup.2 is hydrogen or
C.sub.1 -C.sub.2 alkyl, Y is CO.sub.2 M or SO.sub.3 M, M is an alkali
metal, and n is a number 1 through 3.
Another class of ampholytic surfactants is the amide sulfosuccinates having
the structural formula
##STR2##
The following classes of ampholytic surfactants also can be used:
##STR3##
Additional classes of ampholytic surfactants include the phosphobetaines
and the phosphitaines.
Specific, nonlimiting examples of ampholytic surfactants useful in the
present invention are sodium coconut N-methyl taurate, sodium oleyl
N-methyl taurate, sodium tall oil acid N-methyl taurate, sodium palmitoyl
N-methyl taurate, cocodimethylcarboxymethylbetaine,
lauryldimethylcarboxymethylbetaine, lauryldimethylcarboxyethylbetaine,
cetyldimethylcarboxymethylbetaine,
lauryl-bis-(2-hydroxyethyl)carboxymethylbetaine,
oleyldimethylgammacarboxypropylbetaine,
lauryl-bis-(2-hydroxypropyl)-carboxyethylbetaine,
cocoamidodimethylpropylsultaine, stearylamidodimethylpropylsultaine,
laurylamido-bis-(2-hydroxyethyl)propylsultaine, di-sodium oleamide PEG-2
sulfosuccinate, TEA oleamido PEG-2 sulfosuccinate, disodium oleamide MEA
sulfosuccinate, disodium oleamide MIPA sulfosuccinate, disodium
ricinoleamide MEA sulfosuccinate, disodium undecylenamide MEA
sulfosuccinate, disodium wheat germamido MEA sulfosuccinate, disodium
wheat germamido PEG-2 sulfosuccinate, disodium isostearamideo MEA
sulfosuccinate, cocoamphoglycinate, cocoamphocarboxyglycinate,
lauroamphoglycinate, lauroamphocarboxyglycinate,
capryloamphocarboxyglycinate, cocoamphopropionate,
cocoamphocarboxypropionate, lauroamphocarboxypropionate,
capryloamphocarboxypropionate, dihydroxyethyl tallow glycinate, cocamido
disodium 3-hydroxypropyl phosphobetaine, lauric myristic amido disodium
3-hydroxypropyl phosphobetaine, lauric myristic amido glyceryl
phosphobetaine, lauric myristic amido carboxy disodium 3-hydroxypropyl
phosphobetaine, cocoamido propyl monosodium phosphitaine, lauric myristic
amido propyl monosodium phosphitaine, and mixtures thereof.
Carrier
The carrier of the antibacterial compositions comprises water.
Optional Ingredients
An antibacterial composition of the present invention also can contain
optional ingredients well known to persons skilled in the art. For
example, the composition can contain an active antibacterial agent or an
alcohol. These particular optional ingredients and the amount that can be
present in the composition are discussed hereafter.
The compositions also can contain other optional ingredients, such as dyes
and fragrances, that are present in a sufficient amount to perform their
intended function and do not adversely affect the antibacterial efficacy
of the composition. Such optional ingredients typically are present,
individually, from 0% to about 5%, by weight, of the composition, and,
collectively, from 0% to about 20%, by weight, of the composition.
Classes of optional ingredients include, but are not limited to, dyes,
fragrances, pH adjusters, thickeners, viscosity modifiers, buffering
agents, foam stabilizers, antioxidants, skin conditioners and protectants,
foam enhancers, chelating agents, gelling agents, opacifiers, vitamins,
and similar classes of optional ingredients known to persons skilled in
the art.
Specific classes of optional ingredients include alkanolamides as foam
boosters and stabilizers; gums and polymers as thickening agents; vitamins
A, E, and C as vitamins; inorganic phosphates, sulfates, and carbonates as
buffering agents; polyamino acids and salts, like EDTA and phosphates, as
chelating agents; and acids and bases as pH adjusters.
Examples of preferred classes of basic pH adjusters are ammonia; mono-,
di-, and tri-alkyl amines; mono-, di-, and tri-alkanolamines; alkali metal
and alkaline earth metal hydroxides; and mixtures thereof. However, the
identity of the basic pH adjuster is not limited, and any basic pH
adjuster known in the art can be used. Specific, nonlimiting examples of
basic pH adjusters are ammonia; sodium, potassium, and lithium hydroxide;
monoethanolamine; triethylamine; isopropanolamine; diethanolamine; and
triethanolamine.
Examples of preferred classes of acidic pH adjusters are the mineral acids
and polycarboxylic acids. Nonlimiting examples of mineral acids are
hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid.
Nonlimiting examples of polycarboxylic acids are citric acid, glycolic
acid, and lactic acid. The identity of the acidic pH adjuster is not
limited and any acidic pH adjuster known in the art, alone or in
combination, can be used.
An alkanolamide to provide composition thickening, foam enhancement, and
foam stability can be, but is not limited to, cocamide MEA, cocamide DEA,
soyamide DEA, lauramide DEA, oleamide MIPA, stearamide MEA, myristamide
MEA, lauramide MEA, capramide DEA, ricinoleamide DEA, myristamide DEA,
stearamide DEA, oleylamide DEA, tallowamide DEA, lauramide MIPA,
tallowamide MEA, isostearamide DEA, isostearamide MEA, and mixtures
thereof.
Optional Antibacterial Agent
An active antibacterial agent optionally is present in a composition of the
present invention in an amount of 0% to about 5%, and preferably about
0.01% to about 3%, by weight of the composition. To achieve the full
advantage of the present invention, the antibacterial agent is present in
an amount of about 0.01% to about 1%, by weight, of the composition.
The antibacterial compositions can be ready to use compositions, which
typically contain 0% to about 2%, preferably 0.01% to about 1.5%, and most
preferably about 0.05% to about 1%, of an antibacterial agent, by weight
of the composition. The antibacterial compositions also can be formulated
as concentrates that are diluted before use with one to about 100 parts
water to provide an end use composition. The concentrated compositions
typically contain 0% and up to about 10%, by weight, of the antibacterial
agent. Applications also are envisioned wherein the end use composition
contains greater than 2%, by weight, of the antibacterial agent.
If present at all, a composition of the present invention contains an
amount of antibacterial agent that is at least about 2%, and preferably at
least about 25%, of the saturation concentration of the antibacterial
agent in water, when measured at room temperature. To achieve the full
advantage of the present invention, the continuous aqueous phase is about
50% to 100% saturated with the antibacterial agent. The amount of
antibacterial agent present in the continuous aqueous phase can be defined
as the total amount of antibacterial agent in the composition, less any
antibacterial agent present in surfactant micelles. The method of
determining percent saturation of antibacterial agent in the composition
is disclosed hereafter.
The antimicrobial agents useful in the present invention are phenolic
compounds exemplified by the following classes of compounds:
(a) 2-Hydroxydiphenyl compounds
##STR4##
wherein Y is chlorine or bromine, Z is SO.sub.2 H, NO.sub.2, or C.sub.1
-C.sub.4 alkyl, r is 0 to 3, o is 0 to 3, p is 0 or 1, m is 0 or 1, and n
is 0 or 1.
In preferred embodiments, Y is chlorine or bromine, m is 0, n is 0 or 1, o
is 1 or 2, r is 1 or 2, and p is 0.
In especially preferred embodiments, Y is chlorine, m is 0, n is 0, o is 1,
r is 2, and p is 0.
A particularly useful 2-hydroxydiphenyl compound has the structure:
##STR5##
having the adopted name, triclosan, and available commercially under the
tradename IRGASAN DP100, from Ciba Specialty Chemicals Corp., Greensboro,
N.C. Another useful 2-hydroxydiphenyl compound is
2,2'-dihydroxy-5,5'-dibromodiphenyl ether.
(b) Phenol derivatives
##STR6##
wherein R.sub.1 is hydro, hydroxy, C.sub.1 -C.sub.4 alkyl, chloro, nitro,
phenyl, or benzyl; R.sub.2 is hydro, hydroxy, C.sub.1 -C.sub.6 alkyl, or
halo; R.sub.3 is hydro, C.sub.1 -C.sub.6 alkyl, hydroxy, chloro, nitro, or
a sulfur in the form of an alkali metal salt or ammonium salt; R.sub.4 is
hydro or methyl, and R.sub.5 is hydro or nitro. Halo is bromo or,
preferably, chloro.
Specific examples of phenol derivatives include, but are not limited to,
chlorophenols (o-, m-, p-), 2,4-dichlorophenol, p-nitrophenol, picric
acid, xylenol, p-chloro-m-xylenol, cresols (o-, m-, p-),
p-chloro-m-cresol, pyrocatechol, resorcinol, 4-n-hexylresorcinol,
pyrogallol, phloroglucin, carvacrol, thymol, p-chlorothymol,
o-phenylphenol, o-benzylphenol, p-chloro-o-benzylphenol, phenol,
4-ethylphenol, and 4-phenolsulfonic acid. Other phenol derivatives are
listed in WO 98/55096, incorporated herein by reference.
(c) Diphenyl Compounds
##STR7##
wherein X is sulfur or a methylene group, R.sub.1 and R'.sub.1 are hydroxy,
and R.sub.2, R'.sub.2, R.sub.3, R'.sub.3, R.sub.4 R , R'.sub.4, R.sub.5,
and R'.sub.5, independent of one another, are hydro or halo. Specific,
nonlimiting examples of diphenyl compounds are hexachlorophene,
tetrachlorophene, dichlorophene, 2,3-dihydroxy-5,5'-dichlorodiphenyl
sulfide, 2,2'-dihydroxy-3,3',5,5'-tetrachlorodiphenyl sulfide,
2,2'-dihydroxy-3,5',5,5',6,6'-hexachlorodiphenyl sulfide, and
3,3'-dibromo-5,5'-dichloro-2,2'-dihydroxydiphenylamine. Other diphenyl
compounds are listed in WO 98/55096, incorporated herein by reference.
Optional Alcohol
Antibacterial compositions of the present invention also optionally can
contain 0% to about 20%, by weight, of an alcohol. Preferred embodiments
contain 0% to about 15%, by weight, of an alcohol. Most preferred
embodiments contain 0% to about 10%, by weight, of a disinfecting alcohol.
As defined herein, the term "alcohol" is a water-soluble alcohol containing
one to six carbon atoms. Suitable alcohols include, but are not limited
to, methanol, ethanol, propanol, and isopropyl alcohol.
The alcohol can act as a carrier in conjunction with the water. The alcohol
also can contribute disinfecting properties to the antibacterial
composition.
Optional Gelling Agent
The present antibacterial compositions also can contain 0% to about 5%, by
weight, and preferably 0% to about 3%, by weight, of a gelling agent. To
achieve the full advantage of the present invention, the antibacterial
compositions contain about 0% to about 2.5%, by weight, of a gelling
agent. The antibacterial compositions typically contain a sufficient
amount of optional gelling agent such that the composition is a viscous
liquid, gel, or semisolid that can be easily applied to, and rubbed on,
the skin. Persons skilled in the art are aware of the type and amount of
gelling agent to include in the composition to provide the desired
composition viscosity or consistency.
The term "gelling agent" as used here and hereafter refers to a compound
capable of increasing the viscosity of a water-based composition, or
capable of converting a water-based composition to a gel or semisolid. The
gelling agent, therefore, can be organic in nature, for example, a natural
gum or a synthetic polymer, or can be inorganic in nature. Preferred
gelling agents are natural or synthetic polymers or derivatives of natural
polymers (e.g., polyacrylates, cellulosic gums), like carbomers,
polyquaterniums, and carboxymethylcellulosics (e.g., the METHOCEL.RTM.
products available from Dow Chemical Co., Midland, Mich.).
Optional Skin Conditioners and Protectants
The present antibacterial compositions also can contain optional skin
conditioners and/or protectants. Examples of skin conditioners, include
emollients, such as, cetyl myristate, glyceryl dioleate, isopropyl
myristate, lanolin, methyl laurate, PPG-9 laurate, soy stearyl, octyl
palmitate, and PPG-5 lanoate, for example. The skin conditioner also can
be a humectant, for example, glucamine and pyridoxine glycol, for example.
Occlusive skin conditioners, for example, aluminum lanolate, corn oil,
methicone, coconut oil, stearyl stearate, phenyl trimethicone,
trimyristin, olive oil, and synthetic wax, also can be used. Combinations
of the classes of skin conditioners, in addition to miscellaneous skin
conditioners known to persons skilled in the art, alone or in combination
can be used. Nonlimiting examples of miscellaneous skin conditioners
include aloe, cholesterol, cystine, keratin, lecithin, egg yolk, glycine,
PPG-12, retinol, salicylic acid, orotic acid, vegetable oil, and soluble
animal collagen. The skin conditioners can be used alone, or in
combination with a skin protectant, like petroleum, cocoa butter,
calamine, and kaolin, for example. A skin protectant also can be used
alone. Additional examples of skin conditioners and protectants can be
found in "CTFA Cosmetic Ingredient Handbook," J. M. Nikitakis, ed., The
Cosmetic, Toiletry and Fragrance Association, Inc., Washington, D.C.
(1988) (hereafter CTFA Handbook), pages 79-85, incorporated herein by
reference.
The antibacterial compositions of the present invention do not rely upon a
low pH or a high pH to provide a rapid reduction in bacterial populations.
Antibacterial compositions of the present invention can have a pH of about
4 to about 9, but at the two extremes of this pH range, the compositions
can be irritating to the skin or damaging to other surfaces contacted by
the composition. Accordingly, antibacterial compositions of the present
invention preferably have a pH of about 5 to about 8, and more preferably
about 6 to about 8. To achieve the full advantage of the present
invention, the antibacterial compositions have a pH of about 6.5 to about
7.5.
To demonstrate the new and unexpected results provided by the antibacterial
compositions of the present invention, the following Examples and
Comparative Examples were prepared, and the ability of the compositions to
control Gram positive and Gram negative bacteria was determined. The
weight percentage listed in each of the following examples represents the
actual, or active, weight amount of each ingredient present in the
composition. The compositions were prepared by blending the ingredients,
as understood by those skilled in the art and as described below.
The following materials were used as ingredients in the examples. The
source of each ingredient, and its abbreviation, are summarized below:
a) Alkyl polyglucoside (APG), Henkel Corp., Hoboken, N.J., PLANTAREN 2000N
UP (active=55.53%),
b) Ammonium lauryl sulfate (ALS), Henkel Corp., STANDAPOL A (active
level=28.3%),
c) Ammonium xylene sulfonate (AXS), Stepan Corp., STEPANATE AXS
(active=40%),
d) Cocamidopropyl betaine (CAPB), McIntyre Group, Ltd., Chicago, Ill.,
MACKAM 35-HP (est. 30% active betaine),
e) Dipropylene glycol (DPG), Dow Chemical Co., Midland, Mich.,
f) Isopropyl alcohol (IPA),
g) Monoethanolamine lauryl sulfate (MEALS), Albright & Wilson, Cumbria,
England, EMPICOL LQ 33/F (active=33%),
h) Octylphenol ethoxylate, 9-10 moles EO (TX100), Union Carbide, TRITON-X
100,
i) Potassium cocoate (KCO), McIntyre Group, Ltd., MACKADET 40-K
(active=38.4%),
j) Potassium laurate (KL), prepared from lauric acid (Sigma, #L-4250,
active=99.8%) and potassium hydroxide,
k) Potassium oleate (KO), Norman, Fox & Co., Vernon, Calif., NORFOX KO
(active=approx. 80%),
1) Propylene glycol (PG), Dow Chemical Co., USP Grade (active
level=99.96%),
m) Sodium cocoamphoacetate (SCA), McIntyre Group, Ltd., MACKAM IC-90
(active=approx. 32%),
n) Sodium cumene sulfonate (SCS), Stepan Chemical Co., STEPANATE SCS
(active=44.6%),
o) Sodium lauryl ether sulfate, 1 mole EO (SLES-1), Henkel, STANDAPOL ES-1
(active=25.40%),
p) Sodium lauryl ether sulfate, 2 mole EO (SLES-2), Henkel, STANDAPOL ES-2
(active level=25.71%),
q) Sodium lauryl sulfate/sodium dodecyl sulfate (SLS/SDS), BDH Biochemical,
BDH Ltd., Poole, England, (active=99.0%),
r) Sodium octyl sulfate (SOS), Henkel, STANDAPOL LF (active=32.90%),
s) Sodium xylene sulfonate (SXS), Stepan Chemical Co., STEPANATE SXS
(active level=40-42%),
t) Triclosan (TCS), IRGASAN DP-300, Ciba Specialty Chemicals Corp.,
Greensboro, N.C. (GC assay on lots used=99.8-99.9% active TCS;
mp=56.0-58.0C.),
u) Triethanolamine lauryl sulfate (TEALS), Henkel, STANDAPOL T
(active=40.1%),
v) p-Chloro-m-xylenol (PCMX), NIPACIDE PX-R, Nipa Inc., Wilmington, Del.
(about 100% active), and
w) Water--distilled or deionized.
The following methods were used in the preparation and testing of the
examples:
a) Determination of Rapid Germicidal (Time Kill) Activity of Antibacterial
Products. The activity of antibacterial compositions was measured by the
time kill method, whereby the survival of challenged organisms exposed to
an antibacterial test composition is determined as a function of time. In
this test, a diluted aliquot of the composition is brought into contact
with a known population of test bacteria for a specified time period at a
specified temperature. The test composition is neutralized at the end of
the time period, which arrests the antibacterial activity of the
composition. The percent or, alternatively, log reduction from the
original bacteria population is calculated. In general, the time kill
method is known to those skilled in the art.
The composition can be tested at any concentration from 0-100%. The choice
of which concentration to use is at the discretion of the investigator,
and suitable concentrations are readily determined by those skilled in the
art. For example, viscous samples usually are tested at 50% dilution,
whereas nonviscous samples are not diluted. The test sample is placed in a
sterile 250 ml beaker equipped with a magnetic stirring bar and the sample
volume is brought to 100 ml, if needed, with sterile deionized water. All
testing is performed in triplicate, the results are combined, and the
average log reduction is reported.
The choice of contact time period also is at the discretion of the
investigator. Any contact time period can be chosen. Typical contact times
range from 15 seconds to 5 minutes, with 30 seconds and 1 minute being
typical contact times. The contact temperature also can be any
temperature, typically room temperature, or about 25 degrees Celsius.
The bacterial suspension, or test inoculum, is prepared by growing a
bacterial culture on any appropriate solid media (e.g., agar). The
bacterial population then is washed from the agar with sterile
physiological saline and the population of the bacterial suspension is
adjusted to about 10.sup.8 colony forming units per ml (cfu/ml).
The table below lists the test bacterial cultures used in the following
tests and includes the name of the bacteria, the ATCC (American Type
Culture Collection) identification number, and the abbreviation for the
name of the organism used hereafter.
Organism Name ATCC # Abbreviation
Staphylococcus aureus 6538 S. aureus
Escherichia coli 11229 E. coli
Klebsiella pneumoniae 10031 K. pneum.
Salmonella choleraesuis 10708 S. choler.
S. aureus is a Gram positive bacteria, whereas E. coli, K. pneum, and S.
choler. are Gram negative bacteria.
The beaker containing the test composition is placed in a water bath (if
constant temperature is desired), or placed on a magnetic stirrer (if
ambient laboratory temperature is desired). The sample then is inoculated
with 1.0 ml of the test bacteria suspension. The inoculum is stirred with
the test composition for the predetermined contact time. When the contact
time expires, 1.0 ml of the test composition/bacteria mixture is
transferred into 9.0 ml of Tryptone-Histidine-Tween Neutralizer Solution
(THT). Decimal dilutions to a countable range then are made. The dilutions
can differ for different organisms. Plate selected dilutions in triplicate
on TSA+ plates (TSA+ is Trypticase Soy Agar with Lecithin and Polysorbate
80). The plates then are incubated for 25.+-.2 hours, and the colonies are
counted for the number of survivors and the calculation of percent or log
reduction. The control count (numbers control) is determined by conducting
the procedure as described above with the exception that THT is used in
place of the test composition. The plate counts are converted to cfu/ml
for the numbers control and samples, respectively, by standard
microbiological methods.
The log reduction is calculated using the formula
Log reduction=log.sub.10 (numbers control)-log.sub.10 (test sample
survivors).
The following table correlates percent reduction in bacteria population to
log reduction:
% Reduction Log Reduction
90 1
99 2
99.9 3
99.99 4
99.999 5
b) Preparation of saturated solutions of TCS in water: A four liter flask
was equipped with a 3-inch magnetic stir bar and charged with
approximately 7.5 grams (g) TCS and 3 liters (L) of water. The flask then
was placed in a water bath, stirred, and heated (40-45.degree. C.) for at
least 8 hours. The flask containing the resulting TCS/water suspension was
removed from the water bath, and the warm suspension filtered through a
Coors #32-H porcelain Buchner funnel equipped with Whatman #40 (5.5cm)
filter paper. The filtering assembly was attached to a two liter vacuum
filter flask, and filtration was conducted in batches. The filtrate then
was transferred to another four liter flask and allowed to cool.
Typically, fine needles of TCS crystals formed after the filtrate was
stored at room temperature for a few days.
For some time kill studies, the TCS solution was refiltered at room
temperature before use in the study. For other time kill studies, a small
amount of crystalline TCS was allowed to remain in the test container to
ensure saturation in the event of a temperature change. It was assumed
that TCS crystals present in the time kill test vessel would not affect
test results because crystalline TCS is unavailable to act on the bacteria
(i.e., is not solubilized).
To determine the concentration of TCS in the water solutions, filtered
samples (in triplicate) were analyzed by HPLC. The apparatus used to
filter the solutions was a Whatman AUTOVIAL.RTM., with 0.45 .mu.m PTFE
membrane and glass microfiber prefilter, cat. No. AV125UORG. TCS
concentrations were calculated using a linear regression line fit
(Microsoft EXCEL.RTM. software) to TCS/IPA standards included on the same
HPLC run.
c) Preparation of aqueous TCS/surfactant compositions: A French square
bottle was charged with a solution containing a variable concentration of
a surfactant and 0.3%, by weight, TCS. The mixture was stirred and heated
(35-40.degree. C.) for several hours until the TCS was solubilized.
Variable transformer-controlled heat lamps were used for warming and the
temperature of the solution was monitored with a digital thermometer.
Stirring then was stopped, TCS seed crystals (about 1 mg) were added to
the solution, and the mixture was allowed to stand at about 20.degree. C.
In a few days, crystals were observed on the bottom of solution containers
in which the maximum solubility of TCS was exceeded.
The approximate concentration of surfactant necessary to almost completely
solubilize the 0.3% TCS was determined by use of an experimental design in
which the concentration of surfactant was serially reduced by a factor of
two over a series of test samples until the approximate saturation point
of TCS in the surfactant was observed. Then the difference in
concentration (saturated vs. just solubilized) was halved until a close
endpoint for TCS saturation could be determined. The saturation point of
TCS/surfactant compositions could be effectively estimated with
small-scale (15 to 100 mL) samples, but about 600-800 g samples were
required to obtain reliable final results. The initial ranges, therefore,
were established with small-scale samples, and the final concentrations
were determined using larger-scale samples.
d) Preparation of compositions containing TCS, a polyhydric solvent, and a
hydrotrope: TCS first was dissolved in the solvent used in the
composition. Water then was added to the TCS/solvent composition, followed
by the addition of about 1 mg of TCS seed crystals, and the resulting
mixture was allowed to stand at about 20.degree. C. to crystallize. In
compositions containing a solvent, hydrotrope, and surfactant, the TCS was
dissolved in the solvent as above, and then the hydrotrope and surfactant
were added to the TCS/solvent solution. The resulting mixture then was
diluted to the batch total with water. Adjustment of pH also was
performed, if required. The mixture was stirred at room temperature for
about an hour, seed TCS was added, and the mixture allowed to stand and
crystallize as above. The determination of the TCS saturation point
described above also was used (i.e., halving surfactant concentrations).
Methods similar to the above for determination of maximum additive
concentration have been described in the literature. For example, P. H.
Elworthy et al., "Solubilization by surface-active agents and its
application in chemistry and biological sciences," Chapman and Hall, Ltd.,
London, pp. 62-65 (1968), describes determination of concentrations near
saturation by observing turbidity of the mixture. A similar technique was
used by observing the sample at right angles with a high-intensity light
from a small flashlight equipped with a beam focusing attachment (i.e.,
MINI MAGLITE.RTM. AA, MAG Instruments, California, USA). This method also
was used with solutions very near to saturation to enhance observation of
small amounts of crystals formed on the bottom of containers.
Table 2 summarizes the results of time kill tests performed on TCS/water
compositions. Two series of results, I and II, demonstrate the effect of %
saturation in TCS/water compositions, i.e., that within a given test
series, reduction in % saturation produces a concomitant reduction in time
kill efficacy. Surprisingly, as demonstrated in the following examples, a
composition of the present invention provides an effective time kill
against Gram positive and Gram negative bacteria, even when an active
antibacterial compound is absent from the composition.
TABLE 2
Time Kill Results for Saturated TCS/Water Compositions
LOG REDUCTION
TCS (g/mL) S. aureus E. coli K. pneum.
S. chol.
Sample (by HPLC) 1 min/or t 5 min. 1 min/or t 5 min 1 min/or
t 5 min 1 min/or t 5 min
I 100% sat'd. 9.3 .times. 10.sup.-7 1.07/15s >3.91 0.44/15s >4.06
0.31/15s >4.00
50% sat'd. 3.9 .times. 10.sup.-7 0.03/15s 1.71 0.13/15s 1.15
0.21/15s 2.76
10% sat'd. 6.7 .times. 10.sup.-8 0.03/15s 0.02 0.06/15s 0.08
0/15s 0.14
II 100% sat'd. 9.6 .times. 10.sup.-6 3.93 1.76
2.85 2.15
50% sat'd. 4.9 .times. 10.sup.-6 0.24 0.26
0.35 1.28
Comparing the data in Tables 2 and 3 shows that at the very lowest
concentration of TCS (i.e., 5 to 10 ppm), the efficacy of time kill is
reduced compared to samples containing higher levels of TCS. For example,
a sample in Table 2 containing 0.93 ppm TCS has a log reduction of 0.44
after 15 seconds vs. E. coli, whereas a sample in Table 3 containing 484
ppm TCS had a log reduction of 4.13 after 15 seconds vs. the same
organism. This effect is more apparent at shorter-contact time periods.
Another example, in more complex compositions is illustrated in samples in
Table 3, i.e., 50 ppm TCS (est.)/10%PG/5%SXS vs. 448 ppm TCS
(est.)/20%PG/10%SXS). The sample with the higher TCS concentration showed
at least a log improvement in bacterial reduction after 1 minute.
The data in Table 3 also show differences in efficacy when different
solvents/hydrotropes are used with approximately the same TCS
concentrations. Table 3 further shows that when the amount of hydrotrope
in the composition is less than the amount of polyhydric solvent in the
composition, and the composition is free of an antibacterial agent, the
composition has a poor time-kill efficacy. Table 3 also shows that if the
composition contains only a polyhydric solvent or only a hydrotrope, and
is free of an antibacterial agent, that the composition has a poor
time-kill efficacy.
TABLE 3
TCS in Solvent and/or Hydrotrope Systems
TCS Solvent/ S. aureus E. coli
(ppm) Hydrotrope sec. 1 min. sec. 1 min.
112 17% IPA >4.42 >3.56
(est)
0 17% IPA 0.42 -0.24
110 23.85% PG >4.39 2.37
(est)
342 40.01% PG 4.97.sup.1) /30.sup.2) >5.17 4.29/30 >4.67
484 41.86% PG >3.46/15 >3.46 4.13/15 >4.38
510 42.53% PG >5.17/30 >5.17 4.47/30 >4.67
723 44.20% PG >3.46/15 >3.46 >4.38/15 >4.38
603 45.05% PG >4.69/15 >4.69 4.21/15 >4.65
895 47.52% PG >5.17/30 >5.17 4.42/30 >4.67
1385 50.00% PG >4.49/15 >4.49 4.45/15 >4.65
0 50.00% PG 0.15/15 0.13 0.25/15 0.26
0 75.00% PG 1.20/15 2.35 0.35/15 1.73
63 5% SXS >4.43 0.96
0 5% SXS 0.33 -0.15
57 5% SCS 3.64 0.80
0 5% SCS -0.05 -0.11
448 20% PG/10% >4.14/30 >4.14 >5.25/30 >5.25
(est) SXS
0 20% PG/10% 0.05/30 0.05 1.16/30 1.35
SXS
50 10% PG/5% 3.42 3.18
(est) SXS
0 10% PG/5% 0.05 0.35
SXS
50 10% PG/5% 0.59 4.96
(est) SCS
0 10% PG/5% -0.03 0.96
SCS
502 14.5% DPG/ >3.63/30 >3.63 >4.44/30 >4.44
(est) 10% SXS
0 14.5% DPG/ 0.03.30 0.04 0.26/30 0.17
10% SXS
TCS Solvent/ K. pneum. S. chol.
(ppm) Hydrotrope sec. 1 min. sec. 1 min.
112 17% IPA >4.11 >3.79
(est)
0 17% IPA 0.89 1.23
110 23.85% PG
(est)
342 40.01% PG 4.33/30 5.29 2.52/30 3.51
484 41.86% PG 2.96/15 >3.44 1.14/15 2.31
510 42.53% PG 4.61/30 >5.64 1.56/30 2.27
723 44.20% PG >3.44/15 >3.44 1.29/15 2.59
603 45.05% PG 2.60/15 4.79 1.79/15 >4.50
895 47.52% PG 5.26/30 >5.64 2.92/30 4.33
1385 50.00% PG 3.26/15 >5.04 2.69/15 >4.59
0 50.00% PG 0.54/15 0.63 0.17/15 0.24
0 75.00% PG 1.98/15 >3.44 1.34/15 3.56
63 5% SXS
0 5% SXS
57 5% SCS
0 5% SCS
448 20% PG/10% >4.32/30 >4.32 3.17/30 >3.68
(est) SXS
0 20% PG/10% 0.22/30 0.37 0.25/30 1.29
SXS
50 10% PG/5%
(est) SXS
0 10% PG/5%
SXS
50 10% PG/5%
(est) SCS
0 10% PG/5%
SCS
502 14.5% DPG/ >4.14/30 >4.14 >4.14/30 >4.14
(est) 10% SXS
0 14.5% DPG/ 0.34/30 0.39 0.36/30 0.47
10% SXS
.sup.1) log reduction; and
.sup.2) seconds.
The following examples show the unexpected benefits achieved by
compositions of the present invention.
EXAMPLE 1
This example further demonstrates that neither a polyhydric solvent nor a
hydrotrope by itself, nor a combination of polyhydric solvent and
hydrotrope, provides broad-spectrum, fast-acting, high-efficacy
antibacterial activity.
Log Reduction at 1 minute contact
time
Composition No. Solvent Hydrotrope S. aureus E. coli K. pneum. S.
chol.
1-1 50%.sup.3) PG 0 0.13 0.26 0.63
0.17
1-2 0 5% SXS 0.33 0 -- --
1-3 0 5% SCS 0 0 -- --
1-4 20% PG 10% SXS 0.05 1.35 0.37
1.29
1-5 10% PG 5% SXS 0.05 0.35 -- --
1-6 10% PG 5% SXS 0 0.96 -- --
1-7 14.5% DPG 10% SXS 0.04 0.17 0.39
0.47
1-8 0 7.5% SXS 0.24 0.35 -- --
1-9 0 10% SXS 0.25 0.55 -- --
1-10 0 12.5% SXS 0.12 0.77 -- --
1-11 0 15% SXS 0.36 1.21 -- --
1-12 0 17.5% SXS 0.38 1.37 -- --
1-13 0 20% SXS 0.38 2.84 -- --
.sup.3) % by weight in water
Example 1 clearly shows that a polyhydric solvent alone, even when present
at a high concentration of 50%, is not an effective broad-spectrum
antibacterial agent. Similarly, the hydrotrope alone, and the combination
of polyhydric solvent and hydrotrope, do not provide an effective
antibacterial composition.
EXAMPLE 2
This example demonstrates that a surfactant alone, like a polyhydric
solvent, hydrotrope, or blend of polyhydric solvent and hydrotrope, does
not provide an effective broad-spectrum antibacterial composition.
Composition Log Reduction at 1 minute (time kill)
No. Surfactant.sup.3) S. aureus E. coli K. pneum. S. chol.
2-1 0.048% SLS 0 0 -- --
2-2 0.125% SLS 0.56 0.12 -- --
2-3 0.48% SLS >4 0.67 -- --
2-4 1.6% SLS >3.94 1.51 -- --
2-5 1.35% ALS >3.97 0 -- --
2-6 5% SOS 1.76 >4.47 -- --
2-7 2.5% KO 0 0 -- --
2-8 3% KL 0.18 1.74 -- --
2-9 4% ALS >3.61 0.24 0.15 0.04
.sup.3) % by weight in water
In this example, sodium lauryl sulfate (SLS), ammonium lauryl sulfate
(ALS), and sodium octyl sulfate (SOS) are anionic surfactants, whereas
potassium oleate (KO) and potassium laurate (KL) are anionic potassium
soaps.
EXAMPLE 3
This example demonstrates that anionic, nonionic, and amphoteric
surfactants do not provide fast-acting, broad-spectrum antibacterial
compositions, even when the surfactant is combined with a phenolic
antibacterial agent (i.e., triclosan or TCS).
Log Reduction at
Composition % 1 minute
No. Surfactant % Surfactant.sup.3) TCS.sup.3) S. aureus E. coli
3-1 ALS 1.35 0.3 >3.17 1.39
3-2 MEALS 1.5 0.3 2.29 0.58
3-3 TEALS 1.5 0.3 2.75 1.3
3-4 KCO 1.5 0.3 >4.34 0.35
3-5 KO 1.0 0.3 0.55 0
3-6 KL 3.0 0.3 1.06 0.82
3-7 SLES-1 1.25 0.3 >4.39 0.41
3-8 SLES-2 1.0 0.3 >4.25 0
3-9 TX100 4.0 0.3 0.16 0.43
3-10 SCA 1.25 0.3 0 0
3-11 CAPB 1.25 0.3 0 0.21
3-12 APG 2.5 0.3 0 0.01
.sup.3) % by weight in water
In this example, SCA and CAPB are amphoteric surfactants. TX100 and APG are
nonionic surfactants. MEALS, TEALS, KCO, SLES-1, and SLES-2 are anionic
surfactants. Example 3 clearly shows that a wide range of surfactants when
formulated with an active antibacterial agent do not provide a
fast-acting, broad-spectrum antibacterial composition.
EXAMPLE 4
This example shows that compositions containing a surfactant, a hydrotrope,
and a polyhydric solvent provide a surprisingly fast-acting,
broad-spectrum antibacterial activity. The following table compares
compositions 4-1 through 4-3 to comparative compositions Nos. 1-4 and 2-9.
Log Reduction at 1 minute
contact time
Composition No. Surfactant.sup.3) Solvent.sup.3) Hydrotrope.sup.3) S.
aureus E. coli K. pneum. S. chol.
4-1 0.5% ALS 20% PG 10% SXS 3.84 >4.41
1.49 2.93
2-9 4% ALS 0 0 >3.61 0.24
0.15 0.04
1-4 0 20% PG 10% SXS 0.05 1.35
0.37 1.29
4-2 0.75% ALS 5% DPG 15% AXS 4.24 >4.5
2.57 4.68
4-3 0.75% ALS 5% DPG 0 >2.59 0.5
0.59 0.33
.sup.3) % by weight in water
Example 1-4 shows that a combination of PG and SXS does not provide an
effective antibacterial composition. Overall, Example 1 shows that
polyhydric solvents and hydrotropes alone are not effective in providing
an antibacterial composition. Example 2-9 further shows that even a high
concentration of ALS alone is not effective in providing an antibacterial
composition. Example 4-1, however, illustrates the unexpected property of
a combination of polyhydric solvent, hydrotrope, and surfactant in
providing broad-spectrum, fast-acting antibacterial activity. The
observation that the antibacterial effectiveness of Example 4-1 is not
simply the additive antibacterial properties of 2-9 and 1-4 reveals the
antibacterial synergy provided by the ingredients of a composition of the
present composition, which is both surprising and unexpected.
Examples 4-2 and 4-3 further illustrate the synergistic properties
demonstrated by the present compositions (i.e., Example 4-2) and confirm
that the combination of surfactant and solvent (i.e., Example 4-3) is
insufficient to account for the antibacterial activity of the present
composition.
As illustrated in the following Example 5, the present antibacterial
compositions comprise a polyhydric solvent, such as a glycol, like
dipropylene glycol, a hydrotrope, like sodium xylene sulfonate, and a
surfactant, like ammonium lauryl sulfate. The compositions further
optionally can contain an active antibacterial agent, like triclosan, to
provide a further antibacterial benefit. As illustrated hereafter,
preferred surfactants include anionic surfactants, such as sulfates,
sulfonates, and the like. However, with a judiciously selected combination
of solvent and hydrotrope, any surfactant can be used in a composition of
the present invention. As illustrated hereafter, it surprisingly has been
found that a combination of polyhydric solvent, hydrotrope, and surfactant
provides a highly effective antibacterial composition demonstrating
synergistic activity.
EXAMPLE 5
The following example illustrates compositions of the present invention.
This example demonstrates that when a combination of polyhydric solvent,
hydrotrope, and surfactant are admixed to form a composition of the
present invention, the percent saturation of optional, antibacterial
agent, e.g., triclosan, in the composition can be low, or zero, and the
composition still can demonstrate a high level of antibacterial activity.
The polyhydric solvent used in this example is dipropylene glycol, and the
surfactant is either sodium lauryl sulfate (noted in the following Table 4
by S) or ammonium lauryl sulfate (noted in Table 4 by A). The hydrotrope
is sodium xylene sulfonate. The following Table 4 summarizes the
ingredients present in the compositions and Table 5 summarizes the
antibacterial activity of these compositions, as measured by time kill.
TABLE 4
Composition % TCS.sup.3) % Saturation of TCS % Surfactant.sup.3) %
Polyhydric Solvent.sup.3) % Hydrotrope.sup.3)
A 0.30 100 1.5 (S) 0
0
B 0.30 <25 10 (S) 0
0
C 0.30 70 0.75 (A) 5
15
D 0.30 35 1.5 (A) 5
15
E 0.30 17 3.0 (A) 5
15
F 0.30 8 6.0 (A) 5
15
G 0.30 4 9.0 (A) 5
15
H 0.30 2 12.0 (A) 5
15
I 0.30 70 0.75 (A) 5
15
J 0.30 .about.60 1.0 (A) 7.5
10
K 0.30 .about.75 0.25 (A) 14.4
10
L 0.0 0 0.25 (A) 14.4
10
M 0.0 0 0.75 (A) 5
15
N 0.30 .about.50 0.50 (A) 14.4
10
.sup.3) % by weight in water
TABLE 5
--Time Kill Results--Log Reductions at 30 seconds/1 minute
("--" indicates the composition was not tested)
Composition S. aureus E. coli K. pneum. S. chol.
A --/4.7 .sup. --/0.95 --/2.5 .sup. --/0.92
B --/-- .sup. --/0.85 .sup. --/0.75 --/--
C >4.51/>4.51 >4.63/>4.63 4.38/>4.38 3.33/>3.88
D >4.51/>4.51 >4.63/>4.63 3.01/>4.38 2.95/>3.88
E >3.79/>3.79 >3.93/>3.93 2.87/>4.36 >4.25/>4.25
F >3.79/>3.79 >3.93/>3.93 2.71/>4.36 >4.25/>4.25
G --/-- --/-- >4.04/>4.04 --/--
H --/-- --/-- 3.74/>4.04 --/--
I --/-- --/-- 3.49/>3.69 --/--
J --/-- --/-- 0.17/0.92 --/--
K >4.59/>4.57 >4.70/>4.70 4.06/>4.41 >4.04/>4.04
L 1.7/2.19 3.97/>4.70 0.50/1.43 3.04/>4.04
M 0.79/0.9 >4.34/>4.34 0.41/1.53 >4.04/>4.04
N 4.39/>4.77 >4.71/>4.71 3.00/>4.55 >4.20/>4.20
The compositions of Example 5 demonstrate the surprising and unexpected
synergistic antibacterial activity achieved by a combination of solvent,
hydrotrope, and surfactant. The antibacterial activity can be further
improved by including an optional active antibacterial agent. A surprising
aspect of the present composition is that antibacterial activity is
demonstrated for compositions in which the saturation of antibacterial
agent in the composition is less than about 25% (i.e., compositions E-H),
and even zero. In particular, composition H contains TCS in an amount of
2% of saturation.
Compositions A and B demonstrate that, while some antibacterial activity is
demonstrated by compositions absent a solvent and hydrotrope, the efficacy
of the compositions is limited, even if fully saturated with TCS.
Compositions C-H demonstrate that, in the presence of the synergistic
solvent/hydrotrope/surfactant combination, high efficacy formulations can
be prepared even if the percent saturation of the phenolic antibacterial
agent (i.e., triclosan) in the composition is low, i.e., below 25%.
Compositions I and J illustrate the effect of the hydrotrope/polyhydric
solvent weight ratio. Composition I has a hydrotrope/solvent ratio of 3/1
and is highly effective against the bacteria K. pneum, whereas composition
J has a hydrotrope/solvent ratio of 4/3 and is less effective against the
same bacteria. Compositions K, L, and M are alternative embodiments of the
present invention. Furthermore, examples L and M show that the present
compositions can be formulated without an active antibacterial agent and
still have efficacy against a variety of bacteria. Composition N
illustrates an effective composition of the present invention that is
outside the preferred ratio of hydrotrope to polyhydric solvent.
EXAMPLE 6
The following example illustrates additional compositions of the present
invention. This example compares a series of compositions containing a
synergistic blend of polyhydric solvent, surfactant, and hydrotrope. Some
of the compositions contain triclosan (TCS), and some compositions are
free of an active antibacterial agent. The results illustrate the overall
antibacterial efficacy of the present compositions.
Composition % TCS.sup.3) % DPG.sup.3) % SXS.sup.3) % ALS.sup.3)
A 0.30 5 15 0.75
B 0.0 5 15 0.75
C 0.30 5 15 1.5
D 0.0 5 15 1.5
E 0.30 5 15 3.0
F 0.0 5 15 3.0
The following table summarizes the time kill results against S. aureus and
E. coli for the compositions of Example 6.
Log Reductions at 30 seconds and 1 minute
S. aureus E. coli
Composition 30 seconds 1 minute 30 seconds 1 minute
A >4.49 >4.49 >4.34 >4.34
B 3.25 3.88 >4.34 >4.34
C >4.49 >4.49 >4.34 >4.34
D 3.47 4.09 >4.34 >4.34
E >4.49 >4.49 >4.34 >4.34
F 3.58 4.39 >4.34 >4.34
The data summarized above shows that while all examples A-F exhibit
excellent broad-spectrum antibacterial activity, compositions containing
TCS (i.e., A, C, and F), exhibited slightly superior antibacterial
efficacy and hence are preferred. Thus, the present compositions exhibit
excellent antibacterial efficacy in the absence of an active antibacterial
agent, and including an active antibacterial agent, (i.e., % saturation is
zero) such as TCS, further improves the performance of the present
compositions.
EXAMPLE 7
This example illustrates compositions of the invention that can be used as
hand cleansers. The compositions of this example include embodiments
wherein an antibacterial agent is present in combination with a
surfactant, a polyhydric solvent, and a hydrotrope (i.e., Examples 7-A and
7-B). Additionally, Example 7-C is free of a traditional antibacterial
agent. The following table summarizes the compositions of Example 7, with
the only other ingredient in the compositions being deionized water.
Composition % TCS % DPG % SXS % ALS
7-A 0.30 5 15 1.5
7-B 0.30 5 15 3.0
7-C 0.0 5 15 3.0
The following table contains the results of antibacterial activity of the
compositions of Example 7 by the standard time kill method outlined above.
Log Reduction at 30 seconds
% Saturation contact time
Composition of TCS S. aureus E. coli
7-A 35 >4.49 >4.34
7-B 17 >4.49 >4.34
7-C 0 3.52 >4.34
Examples 7-A through 7-C each exhibited excellent homogeneity and
stability. Examples 7-B and 7-C had superior lather performance in hand
wash evaluations using human volunteers. As revealed by the data presented
above, even Example 7-C, which is free of the active antibacterial agent
triclosan, exhibited a highly effective broad-spectrum antibacterial
efficacy. Additionally, Example 7-B, having a percent saturation of TCS
significantly less than 25%, exhibited excellent broad-spectrum
antibacterial activity. This example illustrates that effective
antibacterial compositions having a low percent saturation of TCS can be
prepared when it is desirable to emphasize other advantages of
compositions having high surfactant concentrations and little to no
antibacterial agent.
EXAMPLE 8
This example illustrates the effect of % saturation of TCS in compositions
containing a hydric solvent, hydrotrope, and surfactant. From the data
summarized in the following table, it is shown that a gain in
antibacterial efficacy (as measured by a time kill test) is associated
with an increasing % saturation of the antibacterial agent in a given type
of composition. The following table shows the effect of varying the
concentration of TCS while the concentration of all other components is
kept constant.
Activity Dependence on % Saturation of TCS in
Hydric Solvent/Hydrotrope/Surfactant Compositions
Log Reduction (Time Kill)
Triclosan Other % S. aureus K. pneum.
%.sup.3) Ingredients.sup.3) Saturation (30 s/60 s) (30 s/60 s)
0.413 5% DPG, 15% 100 >4.55/>4.55 >3.81/>3.81
SXS, 0.75% ALS
0.372 5% DPG, 15% 90 >4.55/>4.55 3.81/>3.81
SXS, 0.75% ALS
0.330 5% DPG, 15% 80 >4.55/>4.55 3.46/>3.81
SXS, 0.75% ALS
0.300 5% DPG, 15% 73 >4.55/>4.55 3.40/>3.81
SXS, 0.75% ALS
0.248 5% DPG, 15% 60 3.02/4.05 2.73/>3.81
SXS, 0.75% ALS
0.207 5% DPG, 15% 50 1.96/3.05 2.45/>3.81
SXS, 0.75% ALS
0.166 5% DPG, 15% 40 1.94/2.15 2.30/>3.81
SXS, 0.75% ALS
0.103 5% DPG, 15% 25 1.72/1.93 1.34/2.78
SXS, 0.75% ALS
.sup.3) % by weight in water
The antibacterial compositions of the present invention have several
practical end uses, including hand cleansers, mouthwashes, surgical
scrubs, body splashes, hand sanitizer gels, and similar personal care
products. Additional types of compositions include foamed compositions,
such as creams, mousses, and the like, and compositions containing organic
and inorganic filler materials, such as emulsions, lotions, creams,
pastes, and the like. The compositions further can be used as an
antibacterial cleanser for hard surfaces, for example, sinks and
countertops in hospitals, food service areas, and meat processing plants.
The present antibacterial compositions can be manufactured as dilute
ready-to-use compositions, or as concentrates that are diluted prior to
use.
The compositions also can be incorporated into a web material to provide an
antibacterial wiping article. The wiping article can be used to clean and
sanitize skin or inanimate surfaces.
The present antimicrobial compositions provide the advantages of a broad
spectrum kill of Gram positive and Gram negative bacteria in short contact
times. The short contact time for a substantial log reduction of bacteria
is important in view of the typical 15 to 60 second time frame used to
cleanse and sanitize the skin and inanimate surfaces.
The present compositions are effective in short contact time because the
compositions do not rely upon a traditional active antibacterial agent to
reduce microbe populations. The composition, therefore, is available to
immediately begin reducing bacterial populations because the antibacterial
agent is not present in surfactant micelles. In addition, an antimicrobial
agent can be omitted from the composition, and the composition still
exhibits excellent antibacterial efficacy.
The following examples illustrate various compositions of the present
invention.
EXAMPLE 9
Hand Wash Composition
A composition in accordance with the instant invention, suitable for use as
a hand wash, was prepared. The composition contained the following
components in their indicated weight percentages:
Ingredient Weight Percent
Triclosan 0.30
Ammonium Lauryl Sulfate 0.50
Dipropylene Glycol 14.4
Sodium Xylene Sulfonate 10.0
Deionized Water q.s.
The composition was prepared by admixing the dipropylene glycol and TCS
until homogeneous (about 5 minutes). After the triclosan was completely
dissolved, as evidenced by the absence of undissolved solid material, the
sodium xylene sulfonate was added to the solution. The resulting mixture
then was stirred to completely dissolve the sodium xylene sulfonate.
Finally, the ammonium lauryl sulfate and water were added to the resulting
solution, and the composition was stirred until homogeneous (about 5
minutes).
The composition had a weight ratio of hydrotrope-to-solvent of about
1:1.44, and was about 50% saturated with triclosan. The composition was
evaluated for antibacterial efficacy by a time kill test against S.
aureus, E. coli, K. pneum, and S. chol., each at a contact time of 30
seconds. The composition exhibited log reductions against the bacteria of
>4.39, >4.71, 3.00, and >4.20, respectively. Thus, the composition
exhibited excellent broad spectrum antibacterial activity. This example
demonstrates that effective embodiments of the invention can be prepared
when the weight ratio of various components is outside the preferred
range. However, as exemplified elsewhere herein, preferred embodiments
offer additional advantages.
EXAMPLE 10
Body Splash Composition
A composition in accordance with the present invention, suitable for use as
a body splash, is prepared using the following ingredients in the
following weight percentages:
Ingredient Weight Percent
Triclosan 0.10
Alkyl Polyglycoside 1
Propylene Glycol 5
Sodium Xylene Sulfonate 15
Fragrance 0.05
Ethanol 25
Deionized Water q.s.
The composition is prepared by combining the triclosan, propylene glycol,
fragrance, and ethanol, and admixing the components until all the
triclosan is dissolved, as evidenced by the absence of undissolved
material. The sodium xylene sulfonate then is added, and the resulting
mixture is stirred until the sodium xylene sulfonate is completely
dissolved. Finally, the alkyl polyglycoside and water are added, and the
mixture is stirred again until homogeneous. The resulting composition
forms a refreshing body splash that provides a desirable level of
bacterial reduction on the skin of the user.
EXAMPLE 11
Wet Wipe Composition
A composition in accordance with the present invention, suitable for
impregnating into a nonwoven material for the preparation of a wet wipe
article, is prepared using the following ingredients in the following
weight percentages:
Ingredient Weight Percent
Triclosan 0.20
Ammonium Lauryl Sulfate 5
Dipropylene Glycol 10
Sodium Xylene Sulfonate 20
Deionized Water q.s.
The composition is prepared by admixing dipropylene glycol and TCS until
homogeneous (about 5 minutes). After the triclosan is completely
dissolved, as evidenced by the absence of undissolved material, the sodium
xylene sulfonate is added to the solution. The resulting mixture then is
stirred to completely dissolve the sodium xylene sulfonate. Finally, the
ammonium lauryl sulfate and water are added to the resulting solution, and
the composition is stirred until homogeneous (about 5 minutes).
A piece of nonwoven cellulosic web material (i.e., a commercial paper
towel) then is dipped into the composition to form a wet wiper article,
suitable for wiping and cleansing surfaces, for example, the hands or an
inanimate surface, such as a countertop. The article forms an excellent
wet wipe with good detergent properties and provides a broad-spectrum
antibacterial activity.
EXAMPLE 12
Hand Wash Composition
A composition in accordance with the present invention, suitable for use as
a hand wash, was prepared. The composition contained the following
components in their indicated weight percentages:
Ingredient Weight Percent
Triclosan 0.30
Ammonium Lauryl Sulfate 6
Dipropylene Glycol 5
Sodium Xylene Sulfonate 15
Deionized Water q.s.
The composition was prepared by admixing the dipropylene glycol and TCS
until homogeneous (about 5 minutes). After the triclosan was completely
dissolved, as evidenced by the absence of undissolved material, the sodium
xylene sulfonate was added to the solution. The resulting mixture then was
stirred to completely dissolve the sodium xylene sulfonate. Finally, the
ammonium lauryl sulfate and water were added to the resulting solution,
and the composition was stirred until homogeneous (about 5 minutes).
The composition had a weight ratio of hydrotrope-to-solvent of 3:1 and was
about 8% saturated with triclosan. The composition was evaluated for
antibacterial efficacy by a time kill test against S. aureus, E. coli, K.
pneum, and S. chol., each at a contact time of 1 minute. The composition
exhibited log reductions against the bacteria of >3.79, >3.93, >4.36, and
>4.25, respectively. Thus, the composition exhibited an excellent broad
spectrum antibacterial activity. The example demonstrates the advantages
of a preferred embodiment of the invention with respect to the weight
ratio of hydrotrope-to-solvent, and the inclusion of an active
antibacterial agent. Furthermore, this examples demonstrates that
effective compositions can be formulated with a higher concentration of
surfactant to achieve additional advantages. For example, this composition
has improved lather properties and a superior in-use lather stability in
hand wash tests using human volunteers.
Obviously, many modifications and variations of the invention as
hereinbefore set forth can be made without departing from the spirit and
scope thereof, and, therefore, only such limitations should be imposed as
are indicated by the appended claims.
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